Drug Information

Drug (ID: DG01532) and It's Reported Resistant Information

• Name: Buparlisib
• Synonyms: Buparlisib; 944396-07-0; NVP-BKM120; BKM120; 5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine; NVP-BKM-120; BKM-120; 1202777-78-3; BKM 120; Buparlisib (BKM120); UNII-0ZM2Z182GD; NVP-BKM 120; BKM120 (NVP-BKM120, Buparlisib); 5-(2,6-dimorpholin-4-ylpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine; 5-[2,6-Di(Morpholin-4-Yl)pyrimidin-4-Yl]-4-(Trifluoromethyl)pyridin-2-Amine; 0ZM2Z182GD; CHEMBL2017974; CHEBI:71954; 944396-07-0 (free base); C18H21F3N6O2; 2-Pyridinamine,5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-(trifluoromethyl)-; 5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-(trifluoromethyl)-2-Pyridinamine; 5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine.; Buparlisib [USAN:INN]; BKM 120NX; SD5; Buparlisib; BKM120; 3sd5; Buparlisib (USAN/INN); QCR-4; BKM-120NX; BKM120-NX; MLS006010984; SCHEMBL146956; GTPL7878; BKM120,NVP-BKM120; AMMD00049; BKM-120 (PI3K); DTXSID50241486; EX-A189; SYN1200; HMS3295I15; HMS3655D16; AOB87379; BKM120 (NVP-BKM120); BKM120 - NVP-BKM120; BDBM50380363; MFCD18251596; NSC754353; NSC799370; s2247; ZINC43154039; 2-Pyridinamine, 5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-(trifluoromethyl)-; AKOS016005372; AM85983; BCP9001011; CCG-264954; CS-0089; DB11666; NSC-754353; NSC-799370; SB16577; NCGC00262604-01; NCGC00262604-08; AC-32077; AS-40568; HY-70063; SMR004702786; DB-079882; FT-0755923; SW218149-2; X7578; A25436; D10584; A892274; J-516601; BRD-K42191735-001-01-2; Q25100534; 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine; 5-(2,6-Di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine; 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine
• Indication:
  In total 8 Indication(s)
  Breast cancer [ICD-11: 2C60]; Phase 3; [1]
  Head and neck cancer [ICD-11: 2D42]; Phase 3; [1]
  Melanoma [ICD-11: 2C30]; Phase 3; [1]
  Melanoma [ICD-11: 2C30]; Phase 3; [1]
  Melanoma [ICD-11: 2C30]; Phase 3; [1]
  Renal cell carcinoma [ICD-11: 2C90]; Phase 3; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Phase 3; [1]
  Ureteral cancer [ICD-11: 2C92]; Phase 3; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Breast cancer [ICD-11: 2C60]; [1]
• Target: .; NOUNIPROTAC; [2]
• Formula: 3
• IsoSMILES: C1COCCN1C2=NC(=NC(=C2)C3=CN=C(C=C3C(F)(F)F)N)N4CCOCC4
• InChI: InChI=1S/C18H21F3N6O2/c19-18(20,21)13-9-15(22)23-11-12(13)14-10-16(26-1-5-28-6-2-26)25-17(24-14)27-3-7-29-8-4-27/h9-11H,1-8H2,(H2,22,23)
• InChIKey: CWHUFRVAEUJCEF-UHFFFAOYSA-N
• PubChem CID: 16654980
• ChEBI ID: CHEBI:71954
• TTD Drug ID: D0FJ9I
• DrugBank ID: DB11666

Type(s) of Resistant Mechanism of This Drug

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Lung cancer [ICD-11: 2C25]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PI3-kinase alpha (PIK3CA) [3]

• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SQCLC SKMES-1 cells; Pleura; Homo sapiens (Human); CVCL_0630
• In Vitro Model: HCC2450 cells; Lung; Homo sapiens (Human); CVCL_5133
• In Vitro Model: H596 cells; Lung; Homo sapiens (Human); CVCL_1571
• In Vivo Model: Balb/c-Nude female xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay

Key Molecule: PI3-kinase alpha (PIK3CA) [3]

• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SQCLC SKMES-1 cells; Pleura; Homo sapiens (Human); CVCL_0630
• In Vitro Model: HCC2450 cells; Lung; Homo sapiens (Human); CVCL_5133
• In Vitro Model: H596 cells; Lung; Homo sapiens (Human); CVCL_1571
• In Vivo Model: Balb/c-Nude female xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PI3-kinase alpha (PIK3CA) [1]

• Molecule Alteration: Missense mutation; p.N345I (c.1034A>T)
• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Ion Torrent sequencing assay
• Experiment for Drug Resistance: IC50 assay; Proliferation assay
• Mechanism Description: Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity.

Key Molecule: PI3-kinase alpha (PIK3CA) [1]

• Molecule Alteration: Missense mutation; p.E39K (c.115G>A)
• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Ion Torrent sequencing assay
• Experiment for Drug Resistance: IC50 assay; Proliferation assay
• Mechanism Description: Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity.

Key Molecule: PI3-kinase alpha (PIK3CA) [1]

• Molecule Alteration: Missense mutation; p.E453K (c.1357G>A)
• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Ion Torrent sequencing assay
• Experiment for Drug Resistance: IC50 assay; Proliferation assay
• Mechanism Description: Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity.

Key Molecule: PI3-kinase alpha (PIK3CA) [1]

• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Ion Torrent sequencing assay
• Experiment for Drug Resistance: IC50 assay; Proliferation assay
• Mechanism Description: Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity.

Key Molecule: PI3-kinase alpha (PIK3CA) [1]

• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Ion Torrent sequencing assay
• Experiment for Drug Resistance: IC50 assay; Proliferation assay
• Mechanism Description: Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity.

Key Molecule: PI3-kinase alpha (PIK3CA) [1]

• Molecule Alteration: Missense mutation; p.G1049R (c.3145G>C)
• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Ion Torrent sequencing assay
• Experiment for Drug Resistance: IC50 assay; Proliferation assay
• Mechanism Description: Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: PI3-kinase alpha (PIK3CA) [4]

• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vivo Model: Athymic mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. In comparison to extracranial disease, increased HER3 expression and phosphorylation in brain lesions. HER3 blockade overcame the resistance of HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [2]

• Molecule Alteration: Missense mutation; p.T798M (c.2393_2394delCAinsTG)
• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vivo Model: Athymic female mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: HER2T798M sequencing assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.T798M (c.2393_2394delCAinsTG) in gene ERBB2 cause the sensitivity of Buparlisib by aberration of the drug's therapeutic target

References

• Ref 1: Characterization of PIK3CA and PIK3R1 somatic mutations in Chinese breast cancer patientsNat Commun. 2018 Apr 10;9(1):1357. doi: 10.1038/s41467-018-03867-9.
• Ref 2: Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2Clin Cancer Res. 2013 Oct 1;19(19):5390-401. doi: 10.1158/1078-0432.CCR-13-1038. Epub 2013 Aug 15.
• Ref 3: Inhibition of PI3K Pathway Reduces Invasiveness and Epithelial-to-Mesenchymal Transition in Squamous Lung Cancer Cell Lines Harboring PIK3CA Gene AlterationsMol Cancer Ther. 2015 Aug;14(8):1916-27. doi: 10.1158/1535-7163.MCT-14-0892. Epub 2015 May 26.
• Ref 4: The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activationSci Transl Med. 2017 May 24;9(391):eaal4682. doi: 10.1126/scitranslmed.aal4682.